tbuckley/cabot-search huggingface dataset:
A phase II trial of pembrolizumab and cabozantinib in patients (pts) with recurrent metastatic head and neck squamous cell carcinoma (RMHNSCC).
Authors: Nabil F. Saba, Asari Ekpenyong, Ashley McCook-Veal, Mihir Patel, Nicole Cherie Schmitt, William A. Stokes, James Edward Bates, Soumon Rudra, Marin Ibrahim Abousaud, Jameel Muzaffar, Kedar Kirtane, Yong Teng, Conor Ernst Steuer, Dong Moon Shin, Yuan Liu, Christine H. Chung
Journal: Journal of Clinical Oncology (2022)

6008 Background: Pembrolizumab (pembro) is an immune checkpoint inhibitor (ICI) approved for treating pts with recurrent/metastatic (RM) HNSCC. Cabozantinib (cabo) is a multiple receptor tyrosine kinase inhibitor (TKI) targeting MET and VEGFR2 shown to reduce tumor growth, metastasis, and angiogenesis and has immuno-modulatory properties. Methods: This is a phase II, open label multi-center, single arm trial evaluating the tolerability and clinical benefit of pembro administered at 200 mg every 3 weeks and cabo 40 mg daily for pts with RM HNSCC who have not received prior ICI. It had a lead-in safety cohort allowing reduction of cabo dose to 20mg daily. Eligible pts had RM HNSCC, deemed incurable, with a tumor PD-L1 CPS &gt; 1, RECIST 1.1 measurable disease, a life expectancy of &gt; 3 months, an Eastern Cooperative Group (ECOG) Performance Status (PS) of 0-1. Enrollment was initiated in March of 2019. We estimated that the ORR will improve to 35% with pembro+ cabo (from a historic of 18%) with a significance level of 0.05 and 80% power. Results: A total of 47 pts were screened, 13 screen failures [cavitation on scan (4), inability to swallow pills (2), other exclusions (7)]; 34 pts were enrolled, 32 were dosed and 31 evaluable (at least one follow-up scan). Pts had cancers of the oropharynx (21, 65%), nasopharynx (6, 19%), larynx/hypopharynx (4, 13%) and oral cavity (1,3%). 32 patients received cabo at 40 mg daily; 13 patients (41%) were dose reduced to 20mg daily [mucositis, increased liver function (LFT) tests, diarrhea]; males (n=29, 90%), median age 63 years (range 53-67); presence of distant metastases (34, 100%); prior radiation (29, 90%), chemotherapy (14, 43%); ECOG PS =0 (16, 50%), 1 (16,50%); HPV/p16 positive (17, 53%), negative (5, 16%), not applicable (10, 29%); the most frequent adverse event (AE) (all grades) was fatigue (16,50.0%), grade 3 or 4 treatment-related AE were increased LFTs, hyponatremia (3, 9.3% each). With a median follow up of 12.7 months (mos) (range 6.9- 20.5 mos), a RECIST 1.1 overall response rate ORR= 45.2% (CR=0; PR=14, 45.2%; SD =14, 45.2%; PD=3.0, 10%) with an overall clinical benefit of 90.4% were observed; The 1-yr OS was 67.7% (95% CI, 42.9%-83.6%; median 22.3 mos) and 1-yr PFS was 51.8% (95% CI, 28.8%-70.7%; median 14.6 mos). Conclusions: This phase II trial of pembro + cabo met its primary endpoint of ORR. The regimen is well-tolerated with very encouraging clinical activity in RM HNSCC and warrants further exploration in this disease. The study was supported by a grant from Exelixis to NFS. Clinical trial information: NCT03468218.
The Worth of a Life
Authors: Michelle Izmaylov
Journal: Annals of Internal Medicine (2022)

On Being a DoctorSeptember 2022The Worth of a LifeMichelle Izmaylov, MDMichelle Izmaylov, MDVanderbilt University Medical Center, Nashville, TennesseeSearch for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/M21-4806 Audio Reading - “The Worth of a Life” Audio. Virginia L. Hood, MD, MPH, a physician from the University of Vermont, reads “The Worth of a Life” by Michelle Izmaylov, MD Your browser does not support the audio element. Audio player progress bar Step backward in current audio track Play current audio trackPause current audio track Step forward in current audio track Mute current audio trackUnmute current audio track 00:00/ SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail They grab you, those words: high yield. You, medical student, are always picking through the advice and medical knowledge your attendings offer you on rounds, concentrating your attention on gathering up the words you think will appear on an examination. Your experiences have led you to recognize what you think matters most: your grade on your next examination.And if you have not yet learned that there are things more important than standardized tests, or whether the paper you are so proud of will be accepted by a high-impact journal, or if an interview committee will recognize the years of ... Author, Article, and Disclosure InformationAuthors: Michelle Izmaylov, MDAffiliations: Vanderbilt University Medical Center, Nashville, TennesseeCorresponding Author: Michelle Izmaylov, MD; e-mail, michelle.l.izmaylov.[email protected]org. PreviousarticleNextarticle Advertisement Audio Reading - “The Worth of a Life” Audio. Virginia L. Hood, MD, MPH, a physician from the University of Vermont, reads “The Worth of a Life” by Michelle Izmaylov, MD Your browser does not support the audio element. Audio player progress bar Step backward in current audio track Play current audio trackPause current audio track Step forward in current audio track Mute current audio trackUnmute current audio track 00:00/ FiguresReferencesRelatedDetails Metrics September 2022Volume 175, Issue 9Page: 1335-1336 ePublished: 20 September 2022 Issue Published: September 2022 Copyright & PermissionsCopyright © 2022 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Making Arrangements
Authors: Sylvia S. Villarreal
Journal: Annals of Internal Medicine (2022)

Ad LibitumSeptember 2022Making ArrangementsSylvia S. Villarreal, MEd, MPHSylvia S. Villarreal, MEd, MPHMcGovern Center for Humanities and Ethics Houston, TexasSearch for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/M21-3906 Audio Reading - “Making Arrangements” Audio. Michael A. Lacombe, MD, Annals Associate Editor, reads “Making Arrangements” by Sylvia S. Villarreal, MEd, MPH Your browser does not support the audio element. Audio player progress bar Step backward in current audio track Play current audio trackPause current audio track Step forward in current audio track Mute current audio trackUnmute current audio track 00:00/ SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Propped on one shoulder, a man lies on the grass.His soft body emanates ease—light glints off his spectacles and rosy scalp.Hours yet till midday, the lush green carpet makes a pleasing daisfor old bones, now warmed by sun.Once in a while his right arm swings up in a lazy arcas he flings weeds and dead grass into a small mound.Passing by, I wonder what his life contained beforethis morning. Was there a briefcase stretched with documentsor perhaps, a stethoscope? And where did the aging white Cadillacnow rusting in the driveway, ferry him in days past?At present, he ... Author, Article, and Disclosure InformationAuthors: Sylvia S. Villarreal, MEd, MPHAffiliations: McGovern Center for Humanities and Ethics Houston, TexasCorresponding Author: Sylvia S. Villarreal, MEd, MPH, 6431 Fannin Street, Suite JJL 410, Houston, TX 77030; e-mail, Sylvia.S.[email protected]tmc.edu. PreviousarticleNextarticle Advertisement Audio Reading - “Making Arrangements” Audio. Michael A. Lacombe, MD, Annals Associate Editor, reads “Making Arrangements” by Sylvia S. Villarreal, MEd, MPH Your browser does not support the audio element. Audio player progress bar Step backward in current audio track Play current audio trackPause current audio track Step forward in current audio track Mute current audio trackUnmute current audio track 00:00/ FiguresReferencesRelatedDetails Metrics September 2022Volume 175, Issue 9Page: 1341 ePublished: 20 September 2022 Issue Published: September 2022 Copyright & PermissionsCopyright © 2022 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Cell Front: The House Calls of Mass Incarceration
Authors: Nathaniel P. Morris
Journal: Annals of Internal Medicine (2022)

On Being a DoctorSeptember 2022Cell Front: The House Calls of Mass IncarcerationNathaniel P. Morris, MDNathaniel P. Morris, MDUniversity of California, San Francisco, San Francisco, CaliforniaSearch for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/M22-1350 Audio Reading - “Cell Front: The House Calls of Mass Incarceration” Audio. Virginia L. Hood, MD, MPH, a physician from the University of Vermont, reads “Cell Front: The House Calls of Mass Incarceration” by Nathaniel P. Morris, MD Your browser does not support the audio element. Audio player progress bar Step backward in current audio track Play current audio trackPause current audio track Step forward in current audio track Mute current audio trackUnmute current audio track 00:00/ SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Long before I decided to pursue medicine, when I was growing up, I saw imagery in movies and magazines of the doctor's house call. In this storied house call, a doctor might drive up to a leafy neighborhood, stethoscope and small bag in hand, bringing the promise of help and comfort to those in need. As a physician caring for incarcerated patients, I have learned that doctors' house calls are often far different from this idealized version, instead taking place at jail and prison cells.For the millions of people incarcerated in the United States every year, cells and bunk ... Author, Article, and Disclosure InformationAuthors: Nathaniel P. Morris, MDAffiliations: University of California, San Francisco, San Francisco, CaliforniaCorresponding Author: 1001 Potrero Avenue, 7M, San Francisco, CA 94110; e-mail, nathaniel.p.[email protected]edu. PreviousarticleNextarticle Advertisement Audio Reading - “Cell Front: The House Calls of Mass Incarceration” Audio. Virginia L. Hood, MD, MPH, a physician from the University of Vermont, reads “Cell Front: The House Calls of Mass Incarceration” by Nathaniel P. Morris, MD Your browser does not support the audio element. Audio player progress bar Step backward in current audio track Play current audio trackPause current audio track Step forward in current audio track Mute current audio trackUnmute current audio track 00:00/ FiguresReferencesRelatedDetails Metrics September 2022Volume 175, Issue 9Page: 1340-1341 ePublished: 20 September 2022 Issue Published: September 2022 Copyright & PermissionsCopyright © 2022 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
The Dodo
Authors: Richard Scott Morehead
Journal: Annals of Internal Medicine (2022)

On Being a DoctorSeptember 2022The DodoRichard Scott Morehead, MDRichard Scott Morehead, MDWest Virginia University School of Medicine—Charleston Division and Charleston Area Medical Center, Charleston, West Virginia (R.S.M.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/M22-1964 Audio Reading - “The Dodo” Audio. Michael A. Lacombe, MD, Annals Associate Editor, reads “The Dodo” by Richard Scott Morehead, MD Your browser does not support the audio element. Audio player progress bar Step backward in current audio track Play current audio trackPause current audio track Step forward in current audio track Mute current audio trackUnmute current audio track 00:00/ SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail For personal reasons, I have been thinking about the dodo. Native only to the island of Mauritius, it became extinct in the mid-17th century, about 150 years after its first recorded contact with people. Being flightless, dodoes were easy prey for humans, pigs, housecats, and other animals that were introduced into their island home. Without natural predators, they were reportedly fearless when encountering humans. This made them easy to capture, a quality that was interpreted as stupidity. Their reputation, such as it was, suffered further harm at the hands of artists, whose depictions showed obese and ungainly birds—features likely produced ... Author, Article, and Disclosure InformationAuthors: Richard Scott Morehead, MDAffiliations: West Virginia University School of Medicine—Charleston Division and Charleston Area Medical Center, Charleston, West Virginia (R.S.M.)Corresponding Author: Richard Scott Morehead, MD, 1 Wildacre Road, Charleston, WV 25314; e-mail, [email protected]wvu.edu. PreviousarticleNextarticle Advertisement Audio Reading - “The Dodo” Audio. Michael A. Lacombe, MD, Annals Associate Editor, reads “The Dodo” by Richard Scott Morehead, MD Your browser does not support the audio element. Audio player progress bar Step backward in current audio track Play current audio trackPause current audio track Step forward in current audio track Mute current audio trackUnmute current audio track 00:00/ FiguresReferencesRelatedDetails Metrics September 2022Volume 175, Issue 9Page: 1338-1339 ePublished: 20 September 2022 Issue Published: September 2022 Copyright & PermissionsCopyright © 2022 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Proteasomal Degradation of TRAF2 Mediates Mitochondrial Dysfunction in Doxorubicin-Cardiomyopathy
Authors: Rimpy Dhingra, Inna Rabinovich-Nikitin, Sonny Rothman, Matthew Guberman, Hongying Gang, Victoria Margulets, Davinder S. Jassal, Keshav Narayan Alagarsamy, Sanjiv Dhingra, Carla Valenzuela Ripoll, Filio Billia, Abhinav Diwan, Ali Javaheri, Lorrie A. Kirshenbaum
Journal: Circulation (2022)

Cytokines such as tumor necrosis factor-α (TNFα) have been implicated in cardiac dysfunction and toxicity associated with doxorubicin (DOX). Although TNFα can elicit different cellular responses, including survival or death, the mechanisms underlying these divergent outcomes in the heart remain cryptic. The E3 ubiquitin ligase TRAF2 (TNF receptor associated factor 2) provides a critical signaling platform for K63-linked polyubiquitination of RIPK1 (receptor interacting protein 1), crucial for nuclear factor-κB (NF-κB) activation by TNFα and survival. Here, we investigate alterations in TNFα-TRAF2-NF-κB signaling in the pathogenesis of DOX cardiotoxicity.Using a combination of in vivo (4 weekly injections of DOX 5 mg·kg-1·wk-1) in C57/BL6J mice and in vitro approaches (rat, mouse, and human inducible pluripotent stem cell-derived cardiac myocytes), we monitored TNFα levels, lactate dehydrogenase, cardiac ultrastructure and function, mitochondrial bioenergetics, and cardiac cell viability.In contrast to vehicle-treated mice, ultrastructural defects, including cytoplasmic swelling, mitochondrial perturbations, and elevated TNFα levels, were observed in the hearts of mice treated with DOX. While investigating the involvement of TNFα in DOX cardiotoxicity, we discovered that NF-κB was readily activated by TNFα. However, TNFα-mediated NF-κB activation was impaired in cardiac myocytes treated with DOX. This coincided with loss of K63- linked polyubiquitination of RIPK1 from the proteasomal degradation of TRAF2. Furthermore, TRAF2 protein abundance was markedly reduced in hearts of patients with cancer treated with DOX. We further established that the reciprocal actions of the ubiquitinating and deubiquitinating enzymes cellular inhibitors of apoptosis 1 and USP19 (ubiquitin-specific peptidase 19), respectively, regulated the proteasomal degradation of TRAF2 in DOX-treated cardiac myocytes. An E3-ligase mutant of cellular inhibitors of apoptosis 1 (H588A) or gain of function of USP19 prevented proteasomal degradation of TRAF2 and DOX-induced cell death. Furthermore, wild-type TRAF2, but not a RING finger mutant defective for K63-linked polyubiquitination of RIPK1, restored NF-κB signaling and suppressed DOX-induced cardiac cell death. Last, cardiomyocyte-restricted expression of TRAF2 (cardiac troponin T-adeno-associated virus 9-TRAF2) in vivo protected against mitochondrial defects and cardiac dysfunction induced by DOX.Our findings reveal a novel signaling axis that functionally connects the cardiotoxic effects of DOX to proteasomal degradation of TRAF2. Disruption of the critical TRAF2 survival pathway by DOX sensitizes cardiac myocytes to TNFα-mediated necrotic cell death and DOX cardiotoxicity.
Reply to M. Lv et al
Authors: Anna C. Singleton, Rebecca Raeside, Karice K. Hyun, Stephanie R. Partridge, Gian Luca Di Tanna, Nashid Hafiz, Qiang Tu, Justin Tat-Ko, Stephanie Che Mun Sum, Kerry A. Sherman, Elisabeth Elder, Julie Redfern
Journal: Journal of Clinical Oncology (2022)
Natural Coevolution of Tumor and Immunoenvironment in Glioblastoma
Authors: Lingxiang Wu, Wei Wu, Junxia Zhang, Zheng Zhao, Liangyu Li, Mengyan Zhu, Min Wu, Fan Wu, Fengqi Zhou, Yuxin Du, Rui-Chao Chai, Wei Zhang, Xiaoguang Qiu, Quanzhong Liu, Ziyu Wang, Jie Li, Kening Li, Apeng Chen, Yinan Jiang, Xiangwei Xiao, Han Zou, Rashmi Srivastava, Tingting Zhang, Yun Cai, Yuan Liang, Bin Huang, Ruohan Zhang, Fan Lin, Lang Hu, Xiuxing Wang, Xu Qian, Sali Lv, Baoli Hu, Siyuan Zheng, Zhibin Hu, Hongbing Shen, Yongping You, Roel G.W. Verhaak, Tao Jiang, Qianghu Wang
Journal: Cancer Discovery (2022)

Abstract Isocitrate dehydrogenase (IDH) wild-type glioblastoma (GBM) has a dismal prognosis. A better understanding of tumor evolution holds the key to developing more effective treatment. Here we study GBM's natural evolutionary trajectory by using rare multifocal samples. We sequenced 61,062 single cells from eight multifocal IDH wild-type primary GBMs and defined a natural evolution signature (NES) of the tumor. We show that the NES significantly associates with the activation of transcription factors that regulate brain development, including MYBL2 and FOSL2. Hypoxia is involved in inducing NES transition potentially via activation of the HIF1A–FOSL2 axis. High-NES tumor cells could recruit and polarize bone marrow–derived macrophages through activation of the FOSL2–ANXA1–FPR1/3 axis. These polarized macrophages can efficiently suppress T-cell activity and accelerate NES transition in tumor cells. Moreover, the polarized macrophages could upregulate CCL2 to induce tumor cell migration. Significance: GBM progression could be induced by hypoxia via the HIF1A–FOSL2 axis. Tumor-derived ANXA1 is associated with recruitment and polarization of bone marrow–derived macrophages to suppress the immunoenvironment. The polarized macrophages promote tumor cell NES transition and migration. This article is highlighted in the In This Issue feature, p. 2711
Cannabidiol attenuates hyperalgesia in a mouse model of sickle cell disease
Authors: Hemanth M. Cherukury, Donovan A. Argueta, Natalie Garcia, Raghda Fouda, Stacy Kiven, Jianxun Lei, Varun Sagi, Graham J. Velasco, Bryant Avalos, Nicholas V. DiPatrizio, Kalpna Gupta
Journal: Blood (2022)
Elucidating the diversity of malignant mesenchymal states in glioblastoma by integrative analysis
Authors: Rony Chanoch-Myers, Adi Wider, Mario L. Suva, Itay Tirosh
Journal: Genome Medicine (2022)

Abstract Background Multiple glioblastoma studies have described a mesenchymal (MES) state, with each study defining the MES program by distinct sets of genes and highlighting distinct functional associations, including both immune activation and suppression. These variable descriptions complicate our understanding of the MES state and its implications. Here, we hypothesize that there is a range of glioma MES states, possibly reflecting distinct prior states in which a MES program can be induced, and/or distinct mechanisms that induce the MES states in those cells. Methods We integrated multiple published single-cell and bulk RNA sequencing datasets and MES signatures to define a core MES program that recurs across studies, as well as multiple function-specific MES signatures that vary across MES cells. We then examined the co-occurrence of these signatures and their associations with genetic and microenvironmental features. Results Based on co-occurrence of MES signatures, we found three main variants of MES states: hypoxia-related (MES-Hyp), astrocyte-related (MES-Ast), and an intermediate state. Notably, the MES states are differentially associated with genetic and microenvironmental features. MES-Hyp is preferentially associated with NF1 deletion, overall macrophage abundance, a high macrophage/microglia ratio, and M2-related macrophages, consistent with previous studies that associated MES with immune suppression. In contrast, MES-Ast is associated with T cell abundance and cytotoxicity, consistent with immune activation through expression of MHC-I/II. Conclusions Diverse MES states occur in glioblastoma. These states share a subset of core genes but differ primarily in their association with hypoxia vs. astrocytic expression programs, and with immune suppression vs. activation, respectively.
When I use a word . . . . Elizabethan
Authors: Jeffrey K Aronson
Journal: BMJ (2022)

The end of the second Elizabethan age prompts reflections on the name Elizabeth. When King George VI died on 6 February 1952, his elder daughter, Princess Elizabeth Alexandra Mary, became queen and chose the title Elizabeth II. The name Elizabeth has its origin in Hebrew, originally as Elisheva, meaning “my God [is] an oath.” The name subsequently became Elizabeth, perhaps through the influence of the word shabbat, meaning the Sabbath. Whether Queen Elizabeth knew this and understood the origin of her name, she lived her life in a way that was consistent with its meaning. Two other Elizabeths, Elizabeth Blackwell and Elizabeth Garrett Anderson, were the first women to become registered medical practitioners in the USA and the UK respectively. A natural language programme intended to function as a psychotherapist was named after Eliza Doolittle, the heroine of George Bernard Shaw’s play <i>Pygmalion</i>. And ELISA is an acronym for enzyme-linked immunosorbent assay, an important method for measuring proteins in biological samples.
Information for Readers
Journal: Hepatology (2022)

HepatologyVolume 76, Issue 4 ISSUE INFORMATIONFree Access Information for Readers First published: 19 September 2022 https://doi.org/10.1002/hep.32783AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume76, Issue4October 2022 RelatedInformation
Asthma Induced by Nickel
Authors: George T. Block
Journal: JAMA (1982)

NICKEL allergy manifest as contact dermatitis has long been recognized. In 1971 McConnell et al<sup>1</sup>reported asthma due to nickel sulfate in a metal-plate worker; a bronchoprovocation challenge test with nickel sulfate duplicated the patient's symptoms, and circulating antibodies were found by hemagglutination tests. We report a second case study of asthma induced by nickel sulfate. <h3>Report of a Case</h3> A 60-year-old metal polisher with a history of contact dermatitis and recent episodes of shortness of breath was referred to our clinic in April 1980 for further evaluation. His medical history was unremarkable. He had stopped smoking at the age of 33 years. He had no history of allergies and knew of none in his family. The patient had been a metal polisher since the age of 24 years and had contact with gold, brass, and nickel. At 49 years he began polishing bumpers and continued this work until